Hepatocellular carcinoma (HCC) is the fifth-most common cancer in the world and the third highest cause of cancer-related mortality globally. HCC develops in patients with chronic hepatitis, either due to chronic hepatitis B or C viral infection or due to inflammation following aflatoxin ingestion, or excessive alcohol consumption. Unfortunately, most HCC patients are first diagnosed with the disease at an advanced stage or present with poor liver function, thereby preventing the use of potentially curative therapies. Thus, treatment options for patients with advanced stage disease are limited to either chemoembolization or systemic therapies, which include sorafenib an oral anti-angiogenic agent that is the current backbone of HCC therapy. Though these approaches have led to improved clinical outcomes, patients remain at high risk of disease recurrence after potentially curative surgery and ablation, and survival remains less than one year for patients with advanced stage disease. As toxic chemotherapies are often not well-tolerated by these patients due to liver dysfunction, novel immune-based therapies such as anti-tumor vaccination and adoptive transfer of tumor-specific cytotoxic T cells (CTL) hold promise; however, their impact on tumor regression remains limited. The lack of efficacy of such therapies implies that HCC has developed multiple strategies of escaping tumor-specific immunity. Developing efficacious immunotherapies for HCC is challenging for clinicians.